Phosphatidylserine receptor BAI1 and apoptotic cells as new promoters of myoblast fusion

Abstract

Skeletal muscle arises from the fusion of precursor myoblasts into multinucleated myofibers1,2. While conserved transcription factors and signaling proteins involved in myogenesis have been identified, upstream regulators are less well understood. Here, we report an unexpected discovery that the membrane protein BAI1, previously linked to recognition of apoptotic cells by phagocytes3, promotes myoblast fusion. Endogenous BAI1 expression increased during myoblast fusion, and BAI1 overexpression enhanced myoblast fusion via signaling through ELMO/Dock180/Rac1 proteins4. During myoblast fusion, a fraction of myoblasts underwent apoptosis and exposed phosphatidylserine (PtdSer), an established ligand for BAI13. Blocking apoptosis potently impaired myoblast fusion, and adding back apoptotic myoblasts restored fusion. Furthermore, primary human myoblasts could be induced to form myotubes by adding apoptotic myoblasts, even under normal growth conditions. In vivo, myofibers from Bai1−/− mice are smaller than wild-type littermates. Muscle regeneration after injury was also impaired in Bai1−/− mice, highlighting a role for BAI1 in mammalian myogenesis. Collectively, these data identify signaling via the phosphatidylserine receptor BAI1 and apoptotic cells as novel promoters of myoblast fusion, with significant implications for muscle development and repair.